Super-Resolution Microscopy Helped to Create the First 3D Model of a Synapse

A glance into a new world for neuroscience: research team from Göttingen present the first scientifically accurate 3D model of a synapse

Synapses are the contacts between nerve cells that allow the flow of information that makes our brains work. However, the molecular architecture of these highly complex structures has been unknown until now. A research team from Göttingen, led by Prof. Silvio O. Rizzoli from the DFG Research Center and Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) of the University Medical Center Göttingen, managed to determine the copy numbers and positions of all important building blocks of a synapse for the first time. This allowed them to reconstruct the first scientifically accurate 3D model of a synapse. This effort has been made possible only by a collaboration of specialists in electron microscopy, super-resolution light microscopy (STED), mass spectrometry, and quantitative bio-chemistry from the UMG, the Max Planck Institute for Biophysical Chemistry, Göttingen, and the Leibniz Institute for Molecular Pharmacology, Berlin.

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A new and undiscovered land in neuroscience

"This 3D model of a synapse opens a new world for neuroscientists," says Prof. Rizzoli, senior author of the publication. Particularly the abundance and distribution of the building blocks have long been terra incognita, an undiscovered land. The model presented by Prof. Rizzoli and his team now shows several hundreds of thousands of individual proteins in correct copy numbers and at their exact localization within the nerve cell.

"The new model shows, for the first time, that widely different numbers of proteins are needed for the different processes occurring in the synapse," says Dr. Benjamin G. Wilhelm, first author of the publication. The new findings reveal: proteins involved in the release of messenger substances (neurotransmitters) from so called synaptic vesicles are present in up to 26,000 copies per synapse. Proteins involved in the opposite process, the recycling of synaptic vesicles, on the other hand, are present in only 1,000-4,000 copies per synapse.

These details help to solve a long-lasting controversy in neuroscience: how many synaptic vesicles within the synapse can be used simultaneously? Apparently, more than enough proteins are present to ensure vesicle release, but the proteins for vesicle recycling are sufficient for only 7–11 % of all vesicles in the synapse. This means that the majority of vesicles in the synapse cannot be used simultaneously.

3D Model of a Synapse – video animation

An impressive video animation has been created from the obtained data to visualize the structure and protein distribution of a synapse:

Reference model for neuroscientists

The most important insight the new model reveals, is however that the copy numbers of proteins involved in the same process scale to an astonishingly high degree. The building blocks of the cell are tightly coordinated to fit together in number, comparable to a highly efficient machinery. This is a very surprising finding and it remains entirely unclear how the cell manages to coordinate the copy numbers of proteins involved in the same process so closely.

The new model will serve as a reference source for neuroscientists of all specializations in the future, and will support future research, since the copy number of proteins can be an important indicator for their relevance. But the research team led by Prof. Rizzoli does not plan to stop there: "Our ultimate goal is to reconstruct an entire nerve cell." Combined with functional studies on the interaction of individual proteins this would allow to simulate cellular function in the future – the creation of a "virtual cell".

Fig. 1: The team of Rizzoli's lab.

New opportunities for medical research

For his approach to study the molecular anatomy of nerve cells, Prof. Rizzoli has already been awarded an ERC Consolidator Grant 2013. "The findings of Prof. Rizzoli are spectacular", says Prof. Dr. Heyo Kroemer, speaker of the UMG board and dean of the Faculty of Medicine. "This highly precise synaptic model will provide completely new possibilities for medical research. This is another example demonstrating that the University Medical Center Göttingen provides attractive conditions for international top-level research." Prof. Mathias Bähr, one of the CNMPB speakers, says “We are very excited that Prof. Rizzoli succeeded in accomplishing this project so fast. This study significantly advances our general understanding of the protein distribution with-in healthy nerve cells. In the future, these findings will contribute to identify anomalies in neuronal anatomy in neurodegenerative diseases, such as Parkinson's disease.”

The project was funded by the European Research Council (ERC) and the Deutsche Forschungsgemeinschaft (DFG). The results have been published in the renowned scientific journal SCIENCE on May 30th 2014. Highlighting the impact of this work, the presented model has been selected as the cover of the respective issue of the SCIENCE journal.